Differences in release and clearance of extracellular dopamine in the striatum after spontaneous or GM1-ganglioside-stimulated recovery from experimental Parkinsonism

PURPOSE: This study was designed to assess differences in dopamine clearance rates and potassium chloride (KCl)-stimulated release in the striatum of cats that had either spontaneously recovered from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinsonism or recovered after receiving GM1 ganglioside treatment. METHODS: A severe Parkinsonian motor disorder was produced in 17 adult cats by administration of MPTP for seven to ten days. Six MPTP-treated cats received daily GM1 administration (30 mg/kg, i.m.) for 6 weeks and eleven MPTP-treated cats were allowed to spontaneously recover over the same period of time. High-speed chronoamperometric electrochemical measurements were obtained from dorsal and ventral striatal regions in all animals. Dopamine clearance rates were obtained by measuring the clearance of pressure-ejected dopamine from the extracellular space and local potassium-induced release was studied by applying KCl to the tissue. RESULTS: Dopamine clearance rates recorded in all striatal areas in GM1-treated cats were significantly faster than dopamine clearance rates recorded in spontaneously recovered cats. In GM1-treated animals, electrochemical signals recorded in response to KCl stimulation were sig-nificantly greater in all striatal areas compared to spontaneously recovered animals. Reduction/oxidation (redox) ratios recorded in GM1- treated animals indicated dopamine to be the predominant electroactive species released in all striatal areas in response to KCl stimulation. Redox ratios recorded in the ventral striatum of spontaneously recovered cats also indicated dopamine to be the predominant electroactive spe-cies released in response to KCl stimulation. However, redox ratios recorded in the dorsal striatum of spontaneosuly recovered cats indicated serotonin to significantly contribute to the recorded signal. CONCLUSIONS: These results support previous observations that volume transmission may predominate dopaminergic signaling in the stria-tum of spontaneously recovered cats and suggest that a greater degree of synaptic transmission is possible in GM1-treated animals. While the functional significance of this partial restoration of dopaminergic synaptic transmission in the striatum remains to be determined, it may under-lie improved behavioral recovery observed following GM1 treatment.     

Spontaneous functional recovery from parkinsonism is not due to reinnervation of the dorsal striatum by residual dopaminergic neurons

Cats exposed to MPTP experience severe motor deficits that spontaneously recover after 4–6 weeks. This recovery occurs despite a persistent deficit (approximately 95%) in dorsal striatal DA levels. To determine whether residual DA neurons that previously did not innervate the dorsal caudate nucleus (CD) have innervated this area in recovered MPTP-treated animals, HRP was injected into the dorsal lateral and dorsal medial CD and the locations of retrogradely labeled neurons in ventral mesencephalon were mapped in normal and recovered MPTP-treated cats. Tyrosine hydroxylase (TH) positive cells were also counted in ventral mesencephalic DA-containing cell groups in normal, symptomatic, and recovered MPTP-treated cats. Results showed no difference in the pattern of HRP labeling in normal and recovered cats except for the loss of labeled substantia-nigra pars compacta (SNc) cells in MPTP-treated cats. Cell counts revealed no significant difference in the degree of TH-positive cell loss in all ventral mesencephalic areas studied in both symptomatic and recovered cats. The results suggest that spontaneous recovery of gross motor function in MPTP-treated cats is most likely not dependent upon reinnervation of the dorsal striatum from residual DAergic neurons.     

MPTP-induced parkinsonism: acceleration of biochemical and behavioral recovery by GM1 ganglioside treatment.

The effects of GM1 ganglioside administration on functional recovery and recovery of caudate nucleus dopamine levels have been assessed in cats made parkinsonian by administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cats made severely parkinsonian by MPTP administration began to show spontaneous functional recovery by the third week after MPTP, as had been observed in previous studies with this model. In contrast, cats with similar initial impairment but which received 3 weeks of GM1 ganglioside treatment (30 mg/kg, i.p. daily) showed an accelerated behavioral recovery, showing significant functional improvement after the first week of GM1 treatment and almost normal function by the end of the third week of treatment. The GM1-treated cats had caudate nucleus dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and HVA levels significantly increased above levels measured in saline-treated MPTP control cats. A second group of cats received MPTP only until the first signs of parkinsonism were observed and thus overall had a less severe initial syndrome than the cats described previously. Again, while all cats showed functional recovery over time, the recovery process was accelerated in GM1-treated cats. GM1 treatment also caused a significant increase in caudate dopamine levels in these cats. These results suggest that GM1 ganglioside administration can result in increased dopamine levels even in the heavily denervated striatum and accelerate functional recovery after an MPTP-induced lesion of the nigrostriatal dopamine system in the cat. This suggests that GM1 or other trophic factor therapies may be fruitful treatment strategies for a disorder of nigrostriatal function such as Parkinson's disease.     

Alterations in dopamine uptake sites and D1 and D2 receptors in cats symptomatic for and recovered from experimental parkinsonism

The administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult cats severely disrupts the dopaminergic innervation of the striatum. Animals display a parkinson-like syndrome, consisting of akinesia, bradykinesia, postural instability, and rigidity, which spontaneously recovers by 4–6 weeks after the last administration of MPTP. In this study we used quantitative receptor autoradiography to examine changes in DA uptake sites and DA receptors in the basal ganglia of normal, and symptomatic and recovered MPTP-treated cats. Consistent with the destruction of the nigrostriatal DA pathway, there was a severe loss of DA uptake sites, labeled with [³H]-mazindol, in the caudate nucleus (64–82%), nucleus accumbens (44%), putamen (63%), and substantia nigra pars compacta (SNc, 53%) of symptomatic cats. Following behavioral recovery, there were no significant changes in DA uptake site density. Significant increases of [³H]-SCH 23390 binding to D1 DA receptors were observed in the dorsal caudate (>24%; P < 0.05) of symptomatic cats and in all regions of the caudate-putamen (>30%; P < 0.05) of recovered animals. [³H]-SCH 23390 binding in tree substantia nigra pars reticulata was half of that in the striatum and showed no changes in symptomatic or recovered animals. No alterations in the binding of [¹²⁵1]-epidepride to D2 receptors was observed in any region of the striatum in either, symptomatic or recovered animals. [¹²⁵1]-Epidepride binding in the SNc was decreased by >36% (P < 0.05) following MPTP treatment. These data show that cats made parkinsonian by MPTP exposure have a significant decrease in the number of DA reuptake sites throughout the striatum and that recovery of sensorimotor function in these animals is not correlated with an increase in the number of striatal reuptake sites. Behavioral recovery, however, does seem to be correlated with a general elevation of Dl receptors throughout the striatal complex. The present data also show that direct correlations between changes in DA receptor regulation after a large DA depleting lesion and behavioral deficits or recovery from those deficits are difficult and that the relationships between DA receptors/transporters and behavior require further study. © 1995 Wiley-Liss, Inc.     

Striatal enkephalin gene expression does not reflect parkinsonian signs

Loss of striatal dopamine has been associated with an increase in striatal enkephalin expression. However, the relationship between increased striatal enkephalin expression and the manifestation of parkinsonian motor deficits is not clear. Administration of MPTP to cats produces a severe parkinsonian condition from which the animals spontaneously recover. Using in situ hybridization histochemistry, preproenkephalin (PPE) mRNA expression was examined in the striatum of cats when normal, symptomatic for or spontaneously recovered from MPTP-induced parkinsonism. In all areas of the striatum, PPE mRNA levels were significantly elevated in animals exhibiting severe parkinsonian motor deficits and remained elevated even after recovery of gross motor functioning. These results show that striatal PPE gene expression and parkinsonian motor deficits are not directly correlated.     

Tyrosine hydroxylase and dopamine transporter expression in residual dopaminergic neurons: potential contributors to spontaneous recovery from experimental Parkinsonism

1-Methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-exposed cats develop severe Parkinsonism that spontaneously resolves in 4-6 weeks. The present study examined the extent to which compensatory changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene and protein expression may underlie this behavioral recovery. In normal cats, TH and DAT protein levels were higher in the dorsal vs. ventral striatum. Expression of DAT and TH mRNA was higher in substantia nigra pars compacta (SNc) than in the ventral tegmental area (VTA). In symptomatic parkinsonian animals, DAT and TH protein levels were significantly decreased in all striatal areas studied. TH and DAT mRNA expression in residual SNc neurons were decreased a mean 32% and 38%, respectively. DAT gene expression in residual VTA neurons in symptomatic animals was decreased 30% whereas TH gene expression was unaffected. In spontaneously recovered cats, TH protein levels were significantly higher than the levels in symptomatic cats only in the ventral striatum, whereas no increase in DAT protein levels were observed in any striatal area. Residual neurons in most ventral mesencephalic regions of recovered cats had increased TH mRNA expression but not increased DAT gene expression, compared with symptomatic animals. Thus, increased TH protein and mRNA and suppression of DAT protein and mRNA expression in the striatum and ventral mesencephalon were associated with functional recovery from MPTP-induced parkinsonism.     

Repeated Exposure to MPTP Does Not Produce a Permanent Movement Disorder in Cats Recovered from MPTP-induced Parkinsonism

The effects of additional MPTP injections on striatal neurochemistry and tyrosine hydroxylase positive cell populations within the ventral mesencephalon in cats recovered from parkinson-like motor deficits resulting from previous MPTP administration was studied. A second or third series of MPTP injections in recovered cats initially reinstated parkinson-like motor deficits. All cats again recovered normalized motor function two to three weeks after MPTP administration. Neurochemical analysis of striatal tissue showed no or only minor differences in dopamine and metabolite levels within most striatal regions sampled between cats which received single ormultiple sets of MPTP injections. Cell count results showed no significant differences betweenthe two MPTP conditions for the majority of the regions studied. These results suggest that the mechanisms responsible for motor recovery from MPTP intoxication in cats can be transientlydisrupted by further exposure to MPTP and that cats do not develop a permanent parkinsonian syndrome from repeated MPTP exposure.     

Striatal preprotachykinin gene expression reflects parkinsonian signs

Striatal preprotachykinin (PPT) gene expression was measured in MPTP-treated cats when symptomatic and during various stages of recovery from parkinsonism using in situ hybridization histochemistry. Animals expressing severe (1 week post-MPTP) or moderate (3 weeks post-MPTP) parkinsonian sensorimotor deficits had significantly reduced striatal PPT mRNA expression. In contrast, fully recovered animals (6 weeks post-MPTP) had striatal PPT mRNA levels that were not significantly different from normal. Thus, PPT gene expression in the striatum appears to reflect presence or absence of sensorimotor deficits in MPTP-treated cats.     

A role of IL-1 in MPTP-induced changes in striatal dopaminergic and serotoninergic transporter binding: clues from interleukin-1 type I receptor-deficient mice

In mice, the MPTP-induced striatal dopaminergic denervation is followed by a spontaneous partial DAT recovery and by serotoninergic hyperinnervation. We show that IL-1RI-deficient mice have a higher DAT decrease in the ventromedial striatum after MPTP and a higher basal serotoninergic innervation of the whole striatum. These data point to a possible role of IL-1RI in the early MPTP-induced structural or functional remodeling of the nigrostriatal dopamine system.     

GM1 ganglioside treatment promotes recovery of striatal dopamine concentrations in the mouse model of MPTP-induced parkinsonism

GM1 ganglioside (GM1) has in the past been reported to promote regenerative sprouting and functional recovery in both central and peripheral nervous systems. The present experiments were performed in order to investigate whether GM1 might have any therapeutic effect on young mice who had been exposed to the Parkinson-producing neurotoxin MPTP. GM1 caused moderate to dramatic increases in striatal dopamine levels, depending upon duration of exposure to GM1, in animals previously exposed to MPTP. Furthermore, the effects of GM1 on enhancing striatal dopamine levels were apparent when GM1 administration was delayed until 3 days after the last MPTP injection was given and these effects were not reversed when GM1 was withdrawn. Tyrosine hydroxylase (TH) immunohistochemistry of the striatum demonstrated increased numbers of TH-positive fibers and TH-positive terminal fields in GM1-treated animals as compared to animals that received only MPTP. TH immunohistochemistry of the substantia nigra revealed little or no loss of parts compacta neurons in the MPTP-treated mice. On the basis of these observations, GM1 appears to increase the dopamine content of the striatum by promoting or stimulating regenerative sprouting of dopaminergic terminals and perhaps collateral sprouting from remaining intact fibers in the MPTP model of Parkinsonism in the young mouse. We suggest that GM1 ganglioside may hold some promise as a potential adjunct in the treatment of Parkinson's Disease.     

MPTP potentiates 3-nitropropionic acid-induced striatal damage in mice: reference to striatonigral degeneration

Striatonigral degeneration (SND) is a parkinsonian disorder due to the combined degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and striatal output neurons. The aims of this study were to explore (1) the behavioral and histopathological consequences of combined MPTP plus 3-nitropropionic acid (3-NP) intoxication in C57/Bl6 mice and (2) its ability to reproduce the neuropathological hallmarks of SND. 3-NP was administered i.p. every 12 h (total dose=450 mg/kg in 9 days) and MPTP i.p. at 10 mg/(kg day) (total dose=90 mg/kg in 9 days). Four groups of mice (n=10) were compared: control, 3-NP alone, MPTP alone, MPTP + 3-NP. Mice intoxicated with 3-NP and MPTP + 3-NP developed motor symptoms, including hindlimb dystonia and clasping, truncal dystonia and impaired balance adjustments. The severity of motor disorder was worse and lasted longer in MPTP + 3-NP-treated mice compared to 3-NP alone, MPTP alone and controls. 3-NP and MPTP + 3-NP-treated mice also displayed altered gait patterns, impaired motor performance on the pole test, rotarod and traversing a beam tasks and activity parameters. Several of these sensorimotor deficits were also more severe and lasted longer in MPTP + 3-NP-treated mice. Histology demonstrated increased neuronal loss along with astrocytic activation (glial fibrillary acid protein, GFAP) and a higher incidence of circumscribed striatal lateral lesions in MPTP + 3-NP-treated mice compared to 3-NP. Neuronal loss and astrocytic activation were increased in the lateral part of the striatum in 3-NP-intoxicated mice while observed both in the medial and lateral part in MPTP + 3-NP-intoxicated mice. There was also a significant loss of SNc dopaminergic neurons and striatal terminals, similar to that in MPTP-treated mice. Altogether, these results suggest that MPTP potentiates striatal damage and behavioral impairments induced by 3-NP intoxication in mice and constitutes a useful model of the motor disorder and its histopathological correlates in SND.     

Behavioral motor recovery in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned squirrel monkey (Saimiri sciureus): changes in striatal dopamine and expression of tyrosine hydroxylase and dopamine transporter proteins

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provides an excellent opportunity to study repair and response to injury in the basal ganglia. Administration to mammals leads to the destruction of nigrostriatal dopaminergic neurons and depletion of striatal dopamine. In the squirrel monkey (Saimiri sciureus), MPTP-lesioning results in parkinsonian motor symptoms including bradykinesia, postural instability, and rigidity. Over time animals display motor behavioral recovery. To better understand this mechanism we employed a lesioning regimen of two or six subcutaneous injections of MPTP (2.0 mg/kg, free-base) to generate mild or moderate parkinsonism. Brain tissue was harvested at 6 weeks or 9 months after the last injection and analyzed for dopamine and its metabolites by high performance liquid chromatography (HPLC), and by immunohistochemical staining and Western immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine- and cAMP-responsive protein phosphatase of 32 kDa (DARPP-32), an effector molecule enriched in striatal medium spiny neurons. Several months after MPTP-lesioning, when squirrel monkeys displayed full motor behavioral recovery, striatal dopamine levels remained low with a greater return in the ventral striatum. This finding is consistent with other reports using neurotoxicant-lesioning models of the basal ganglia in rodents and other species of nonhuman primates. Elevated dopamine turnover ratio and decreased DAT expression appeared in early behavioral recovery at the 6-week time point in both mild- and moderate-parkinsonian monkeys. Tyrosine hydroxylase and DAT expression was increased in late stage recovery even within dopamine-depleted regions and supports sprouting. Altered DARPP-32 expression suggests a role of medium spiny neurons in recovery.     

Production of a Parkinson-like syndrome in the cat with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): behavior, histology, and biochemistry

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a potent dopaminergic neurotoxin, was administered to cats systemically for 5 to 7 days. This treatment produced a behavioral syndrome characterized by akinesia, ataxia, bradykinesia, and feeding difficulties, lasting for several weeks. During this period of severe behavioral impairment, caudate and nucleus accumbens dopamine and norepinephrine concentrations were quite depleted. Behavioral recovery ensued over the next several weeks as did some recovery of striatal catecholamines. MPTP destroyed the majority of substantia nigra pars compacta neurons while affecting a much lesser number of locus ceruleus and ventral tegmental neurons. These results demonstrated for the first time that MPTP can cause long-lasting deficits in nigrostriatal functioning in the cat and may provide a means for studying the apparently selective neurotoxic effects of MPTP as well as for understanding the pathophysiology of Parkinson's disease.     

Recovery of function and basal ganglia [14C]2-deoxyglucose uptake after nigrostriatal injury

Rats with unilateral 6-hydroxydopamine injections along the mesotelencephalic dopaminergic projection showed a profound impairment in localizing somatosensory stimuli on the contralateral body surface at 3 days postoperatively. Approximately one-half of the affected animals recovered the ability to localize tactile stimuli during 6 weeks postoperatively, whereas the remainder did not. When it occurred, the recovery of sensorimotor function began between the third and fifth day postoperatively and plateaued between days 14 and 21. Unilateral damage to these dopaminergic neurons resulted in hemispheric asymmetries of [14C]2-deoxyglucose incorporation at 3 days postoperatively. For structures that normally receive a dopaminergic innervation (e.g., neostriatum, nucleus accumbens septi, olfactory tubercle) the autoradiographic density of the injured side was decreased relative to the intact hemisphere. For structures that receive striatal inputs (globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), the autoradiographic density was increased on the side of the injury. This pattern of altered [14C]2-deoxyglucose incorporation was still present at 6 weeks postoperatively in animals that showed no recovery of somatosensory localization during that time. In contrast, rats that did recover showed no hemispheric asymmetries within the anterior neostriatum, globus pallidus, or substantia nigra pars reticulata at 6 weeks postoperatively, and the time course of normalization of metabolic activity in these structures was similar to that for behavioral restoration. These results directly demonstrate the importance of the neostriatum and particular structures efferent to it in the recovery of sensorimotor functions after striatal dopamine depletion. The types of neuronal plasticity within this basal ganglia circuitry responsible for the normalization of [14C]2-deoxyglucose incorporation and behavior are discussed.     

Behavioral study after local injection of 6-hydroxydopamine into the nucleus accumbens in the rat

Anatomically, the nucleus accumbens (n.Acc.) has been considered as an interface between limbic and striatal sensorimotor structures. In the light of this hypothesis we have investigated the behavioral effects of destruction of the dopaminergic innervation of the n.Acc. after local injection of 6-hydroxydopamine. The following behavioral deficits were observed: hypoexploration in a 4-hole box and 2-compartment field, failure to inhibit response strategies either with positive reinforcement in a straight alley test or negative reinforcement in a passive avoidance test. These disturbances comprise a syndrome of perseveration, reduced distraction by irrelevant information, decreased behavioral switching and flexibility, and a paradoxical locomotor disinhibition in an emotional context. Very similar behavioral changes are found following lesions of limbic structures. In addition, these lesioned animals exhibit an enhanced latency to initiate motor responses. This deficit of behavioral initiation is classically observed in motor striatal disease. It is suggested that the n.Acc. is a key structure for the integration of limbic and striatal sensorimotor functions.     

Recovery of function and basal ganglia [C]2-deoxyglucose uptake after nigrostriatal injury

Rats with unilateral 6-hydroxydopamine injections along the mesotelencephalic dopaminergic projection showed a profound impairment in localizing somatosensory stimuli on the contralateral body surface at 3 days postoperatively. Approximately one-half of the affected animals recovered the ability to localize tactile stimuli during 6 weeks postoperatively, whereas the remainder did not. When it occurred, the recovery of sensorimotor function began between the third and fifth day postoperatively and plateaued between days 14 and 21.Unilateral damage to these dopaminergic neurons resulted in hemispheric asymmetries of [¹⁴C]2-deoxyglucose incorporation at 3 days postoperatively. For structures that normally receive a dopaminergic innervation (e.g., neostriatum, nucleus accumbens septi, olfactory tubercle) the autoradiographic density of the injured side was decreased relative to the intact hemisphere. For structures that receive striatal inputs (globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), the autoradiographic density was increased on the side of the injury.This pattern of altered [¹⁴C]2-deoxyglucose incorporation was still present at 6 weeks postoperatively in animals that showed no recovery of somatosensory localization during that time. In contrast, rats that did recover showed no hemispheric asymmetries within the anterior neostriatum, globus pallidus, or substantia nigra pars reticulata at 6 weeks postoperatively, and the time course of normalization of metabolic activity in these structures was similar to that for behavioral restoration.These results directly demonstrate the importance of the neostriatum and particular structures efferent to it in the recovery of sensorimotor functions after striatal dopamine depletion. The types of neuronal plasticity within this basal ganglia circuitry responsible for the normalization of [¹⁴C]2-deoxyglucose incorporation and behavior are discussed.     

Responses of striatal neurons to peripheral sensory stimulation in symptomatic MPTP-exposed cats

Extracellular single unit activity was recorded in the dorsal lateral caudate nucleus of awake cats and the responses of these neurons to somatosensory, visual and auditory stimuli were assessed. Recordings were obtained when animals were normal and when they were symptomatic for a Parkinson-like syndrome as a result of exposure to the dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In normal animals, 22% of recorded neurons responded to tactile stimulation of the face, 7% had auditory responses, 6% had visual responses, and 6% were multimodal. The post-MPTP period was divided into an 'early' period, in which cats had received several MPTP injections but still remained asymptomatic, and a 'late' period, in which cats had severe motor and sensorimotor impairments. Unit responsiveness was essentially normal in the 'early' period but grossly abnormal in the 'late' period. When animals were symptomatic, only 6% of sampled neurons had responses to somatosensory stimulation, 0.8% had auditory responses and no cells were found with visual responses. Those cells that did respond to somatosensory stimulation did so in a non-specific fashion. Symptomatic animals had 93-96% depletion of dorsal striatal dopamine and extensive loss of substantia nigra pars compacta neurons. The results suggest that sensorimotor and motor abnormalities that accompany severe loss of striatal dopamine are at least in part due to a dopamine-dependent loss of sensory processing abilities of striatal neurons.     

3-Acetylpyridine results in degeneration of the extrapyramidal and cerebellar motor systems: loss of the dorsolateral striatal dopamine innervation

3-Acetylpyridine (3-AP) administration to rats results in degeneration of the dopamine (DA) innervation of the striatum as well as degeneration of the olivocerebellar system. We now report that administration of this pyridine neurotoxin results in a decrease in striatal DA concentration which is restricted to the dorsolateral aspects of the caudatoputamen. 3-AP treatment did not alter DA levels in the ventromedial striatum, the nucleus accumbens, or the anteromedial prefrontal cortex. Both 3-AP and another pyridine neurotoxin, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), potently inhibited in vitro MAOB activity and in contrast weakly inhibited MAOA activity. However, in vitro inhibition of MAOB by the selective inhibitor deprenyl did not prevent or attenuate 3-AP-induced striatal DA depletion. These data indicate that 3-AP administration to rats not only results in degeneration of the olivocerebellar system, but also effects degeneration of the DA innervation of the dorsolateral striatum, the striatal sector thought to subserve motoric and sensorimotor function. 3-AP-induced nigrostriatal degeneration differs from that elicited by MPTP in that the former is not prevented by deprenyl pretreatment. The 3-AP-induced degeneration of both extrapyramidal and cerebellar motor systems may offer insight into the mechanisms involved in degeneration of the two motor systems in certain strains of rodents (such as the Weaver mutant mouse), and suggests that the sequelae of administration of this pyridine may serve as a useful model for olivopontocerebellar atrophy-associated parkinsonism.     

Effects of D-cycloserine on MPTP-induced behavioral and neurological changes: potential for treatment of Parkinson's disease dementia

Glutamatergic dysfunction has been implicated in the neurodegeneration seen in Parkinson's disease (PD). Sub-chronic intraperitoneal injection with D-cycloserine (DCS), a partial agonist at the glycine binding site of the N-methyl-D-aspartate (NMDA) receptor, at dosages of 30, 100, or 200 mg/kg/day, was used to evaluate the role of NMDA receptors in neuronal and behavioral changes in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Starting one day after intra-nigral infusion of MPTP, transient disturbance of motor function in the rotarod test was observed. This impairment spontaneously recovered to control levels 6 days after MPTP lesioning and DCS treatment facilitated recovery. MPTP lesioning also caused deficits in working memory and anxiety-like behavior in the T-maze and elevated plus-maze tests, respectively. Further, object recognition was disrupted in MPTP-lesioned rats, and interleukin-2 levels in the striatum, amygdala, and non-prefrontal cortex were increased, both changes being restored by DCS treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration, microglial activation, and cell loss in the hippocampal CA1 area were all improved by DCS treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunctions and that DCS may have clinical potential in the treatment of dementia associated with PD.     

Quantitative analysis of dopaminergic loss in relation to functional territories in MPTP-treated monkeys

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in primates results in a heterogeneous loss of dopamine in the striatum, predominating in the dorsal and caudal parts of the structure, causing functional impairment that appears to be essentially motor and cognitive. The aim of the present study was to quantify the loss of dopamine in relation to the anatomo-functional subdivisions of the striatum, and also of the pallidum and cortex of MPTP-treated monkeys. A severe loss of dopaminergic innervation was observed in both the sensorimotor and associative territories of all these structures in MPTP-treated monkeys. Comparatively, the limbic territories of all these structures were little affected. The preservation of dopaminergic innervation of the limbic part of cerebral structures may explain the preservation of motivational processes mediated by these limbic regions in MPTP-treated monkeys.